Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways. (JXCG . (IS) practice unclear study ultrahigh ultra high chromatographyhigh chromatography UHPLCHRMS. UHPLCHRMS UHPLC HRMS (UHPLC-HRMS) Ultrahigh Ultra chromatographytandem tandem timeofflight time flight UHPLCQTOF Q TOF MS Cytoscape vivo immunoblotting Notably proteins (IS (UHPLC-HRMS

Abstract The incidence of non-alcoholic fatty liver (NAFLD) remains high, and many NAFLD patients suffer from severe ischemia-reperfusion injury (IRI). Currently, no practical approach can be used to treat IRI. Puerarin plays a vital role in treating multiple diseases, such as NAFLD, stroke, diabetes, and high blood pressure. However, its role in the IRI of the fatty liver is still unclear. We aimed to explore whether puerarin could protect the fatty liver from IRI. C57BL/6J mice were fed with a high‐fat diet (HFD) followed by ischemia reperfusion injury. We showed that hepatic IRI was more severe in the fatty liver compared with the normal liver, and puerarin could significantly protect the fatty liver against IRI and alleviate oxidative stress. The PI3K-AKT signaling pathway was activated during IRI, while liver steatosis decreased the level of activation. Puerarin significantly protected the fatty liver from IRI by reactivating the PI3K-AKT signaling pathway. However, LY294002, a PI3K-AKT inhibitor, attenuated the protective effect of puerarin. In conclusion, puerarin could significantly protect the fatty liver against IRI by activating the PI3K-AKT signaling pathway. nonalcoholic non alcoholic (NAFLD ischemiareperfusion . (IRI) Currently diseases stroke diabetes pressure However unclear C57BL6J CBLJ C57BL 6J C BL J highfat fat HFD (HFD stress PI3KAKT PIKAKT PI3K AKT PI K activation LY294002 LY inhibitor conclusion (IRI CBL KAKT PIK LY29400 LY2940 LY294 LY29 LY2

The objective of this study was to assess the efficacy of whole-body vibration (WBV) on bone mineral density (BMD), pain levels, and body composition in postmenopausal women with osteoporosis (PMOP). Relevant studies were retrieved from the PubMed, EMBASE, Web of science, CENTRAL, and PEDro databases. Thirteen randomized controlled trials with 783 patients were enrolled. The meta-analysis results showed that WBV can significantly increase lumbar spine BMD (WMD=0.018; 95%CI: 0.004 to 0.032; P=0.011), femoral neck BMD (WMD=0.005, 95%CI: 0.001 to 0.011, P=0.0493), and reduce pain degree (WMD=-0.786; 95%CI: -1.300 to -0.272; P=0.0027) in PMOP, but has no significant effect on patients' muscle mass (WMD=0.547; 95%CI: -1.104 to 2.199; P=0.5158) as well as fat mass (WMD=0.530; 95%CI: -2.389 to 3.448; P=0.7222). To conclude, WBV showed the potential to provide positive benefits in improving BMD and relieving pain of PMOP. wholebody whole (WBV BMD, , (BMD) levels PMOP . (PMOP) PubMed EMBASE science CENTRAL databases 78 enrolled metaanalysis meta analysis WMD=0.018 WMD0018 WMD 0 018 (WMD=0.018 95%CI 95CI CI 95 0004 004 0.00 0.032 0032 032 P=0.011, P0011 P P=0.011 011 P=0.011) WMD=0.005, WMD0005 005 (WMD=0.005 0001 001 0011 0.011 P=0.0493, P00493 P=0.0493 0493 P=0.0493) WMD=0.786 WMD0786 WMD= 0.786 786 (WMD=-0.786 1.300 1300 1 300 -1.30 0.272 0272 272 -0.272 P=0.0027 P00027 0027 WMD=0.547 WMD0547 547 (WMD=0.547 1.104 1104 104 -1.10 2.199 2199 2 199 P=0.5158 P05158 5158 WMD=0.530 WMD0530 530 (WMD=0.530 2.389 2389 389 -2.38 3.448 3448 3 448 P=0.7222. P07222 P=0.7222 7222 P=0.7222) conclude (BMD (PMOP 7 WMD=0.01 WMD001 01 (WMD=0.01 9 000 00 0.0 0.03 003 03 P001 P=0.01 WMD=0.005 WMD000 (WMD=0.00 0.01 P0049 P=0.049 049 WMD=0.78 WMD078 0786 0.78 (WMD=-0.78 1.30 130 30 -1.3 0.27 027 27 -0.27 P=0.002 P0002 002 WMD=0.54 WMD054 54 (WMD=0.54 1.10 110 10 -1.1 2.19 219 19 P=0.515 P0515 515 WMD=0.53 WMD053 53 (WMD=0.53 2.38 238 38 -2.3 3.44 344 44 P0722 P=0.722 722 WMD=0.0 WMD00 (WMD=0.0 0. P00 P=0.0 WMD=0.00 P004 P=0.04 04 WMD=0.7 WMD07 078 0.7 (WMD=-0.7 1.3 13 -1. 0.2 02 -0.2 P=0.00 P000 WMD=0.5 WMD05 5 (WMD=0.5 1.1 11 2.1 21 P=0.51 P051 51 2.3 23 -2. 3.4 34 4 P072 P=0.72 72 WMD=0. WMD0 (WMD=0. P0 P=0. 07 (WMD=-0. 1. -1 -0. 2. P=0.5 P05 -2 3. P07 P=0.7 WMD=0 (WMD=0 P=0 (WMD=-0 - -0 (WMD= P= (WMD=- (WMD

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a critical respiratory syndrome with limited effective interventions. Lung macrophages play a critical role in the pathogenesis of abnormal inflammatory response in the syndrome. Recently, impaired fatty acid oxidation (FAO), one of the key lipid metabolic signalings, was found to participate in the onset and development of various lung diseases, including ALI/ARDS. Lipid/fatty acid contents within mouse lungs were quantified using the Oil Red O staining. The protective effect of FAO activator L-carnitine (Lca, 50, 500, or 5 mg/mL) was evaluated by cell counting kit 8 (CCK-8) assay, real-time quantitative PCR (qPCR), ELISA, immunoblotting, fluorescence imaging, and fluorescence plate reader detection in lipopolysaccharide (LPS) (100 ng/mL)-stimulated THP-1-derived macrophages. The in vivo efficacy of Lca (300 mg/kg) was determined in a 10 mg/kg LPS-induced ALI mouse model. We found for the first time that lipid accumulation in pulmonary macrophages was significantly increased in a classical ALI murine model, which indicated disrupted FAO induced by LPS. Lca showed potent anti-inflammatory and antioxidative effects on THP-1 derived macrophages upon LPS stimulation. Mechanistically, Lca was able to maintain FAO, mitochondrial activity, and ameliorate mitochondrial dynamics. In the LPS-induced ALI mouse model, we further discovered that Lca inhibited neutrophilic inflammation and decreased diffuse damage, which might be due to the preservation of mitochondrial homeostasis. These results broadened our understanding of ALI/ARDS pathogenesis and provided a promising drug candidate for this syndrome.

This research investigated the predictive value of combined detection of brain natriuretic peptide (BNP) and cystatin C (Cys C) in heart failure after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). Sixty-five AMI patients complicated by heart failure (HF) after PCI and 79 non-heart failure (non-HF) patients were involved in this research. The levels of Cys C and BNP were measured. Risk factors for heart failure in AMI patients after PCI were analyzed by multivariate logistic regression analysis. Efficacy of BNP and Cys C on predicting heart failure were analyzed by receiver operating characteristic (ROC) curve. Cys C and BNP levels were significantly higher in the HF group than in the non-HF group. BNP and Cys C levels were the independent influencing factors causing heart failure within one year after PCI. The area under the predicted curve (AUC) of Cys C, BNP, and combined Cys C and BNP were 0.763, 0.829, and 0.893, respectively. The combined detection of Cys C and BNP was highly valuable in predicting heart failure in AMI patients after PCI, which can be regarded as the serum markers for diagnosis and treatment of heart failure.

Pulmonary fibrosis (PF) is a major public health issue with limited treatment options. As the active ingredient of the n-butanol extract of Amygdalus mongolica (BUT), amygdalin inhibits PF. However, its mechanisms of action are unclear and need further verification. Therefore, the purpose of the present studies was to investigate the anti-fibrotic effects of BUT on PF by serum metabolomics and the transforming growth factor β (TGF-β) pathway. Sixty male Sprague-Dawley rats were randomly divided into control, untreated PF, prednisone-treated (5 mg/kg), and BUT-treated (1.75, 1.25, 0.75 g/kg) groups, and the respective drugs were administered intragastrically for 21 days. The serum metabolomics profiles were determined by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) and metabolism network analysis. The expression of TGF-β1, Smad-3, Smad-7, and α-smooth muscle actin (α-SMA) was measured using a real-time polymerase chain reaction in the lung tissue. BUT significantly alleviated fibrosis by reducing the mRNA expressions of TGF-β1 (from 1.73 to 1.13), Smad-3 (from 2.01 to 1.19), and α-SMA (from 2.14 to 1.19) and increasing that of Smad7 (from 0.17 to 0.62). Twenty-eight potential biomarkers associated with PF were identified. In addition, four key biomarkers were restored to baseline levels following BUT treatment, with the lowest dose showing optimal effect. Furthermore, A. mongolica BUT was found to improve PF by the pentose phosphate pathway and by taurine, hypotaurine, and arachidonic acid metabolism. These findings revealed the mechanism of A. mongolica BUT antifibrotic effects and metabolic activity in PF rats and provided the experimental basis for its clinical application.

ABSTRACT Chicken abdominal fat (AF) is an economically important trait, and many studies have been conducted on genetic selection for AF. However, previous studies have focused on detecting functional chromosome mutations or regions using gene chips. The present study used the specific-locus amplified fragment sequencing (SLAF-seq) technology to perform a genome-wide association study (GWAS) on purebred Wengshang Barred chicken. A total of 1,286,715 single-nucleotide polymorphisms (SNPs) were detected, and 175,211 SNPs were selected as candidate SNPs for genome-wide association analysis using TASSEL general linear models. Two SNPs markers reached genome-wide significance. Of these, rs7943847, rs127627362 were significantly associated with AF at 120 days. These SNPs are close to eight genes (SLC16A6, ARSG, WIPI1, PRKAR1A, FAM20A, ABCA8, ABCA9, CPQ,). These results would enrich the studies on AF and promote the use of Chinese chicken, especially the Wenshang Barred chicken.

ABSTRACT Objective: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. Materials and Methods: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. Results: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. Conclusion: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.

ABSTRACT The effects of plant essential oil (PEO) on the production performance and immune function of laying hens were evaluated to provide theoretical basis for promoting the natural plant extracts. Eight thousand 1-day-old healthy laying hens were randomly divided into a control group or PEO group, with four replicates per treatment and 1000 hens per replicate. The PEO diet was supplemented with 3g/kg plant extract. Diets were fed for 56 days. The tibia length and keel length were detected on an empty stomach at the end of the trial. Blood samples were collected on the 28th and 56th days to detect the level of C3, C4, IL-1, IL-2, IL-17 and immunoglobulin in the serum. The results showed that, compared with the control, PEO supplementation significantly increased the weight gain rate (WGR) at the 2nd, 4th, 5th and 7th week (p<0.05), and decreased the WGR at the 3rd and 6th week. The tibial length was significantly increased at the 3rd, 5th, 6th and 7th week (p<0.01), and also the keel length at the 5th and 7th week in PEO group. The concentration of IgG and IgM also significantly influenced with PEO supplementation, but there was no significant difference in the complements, C3 and C4, and the IL levels between days 28 and 56. Moreover, no significant difference was observed in body weight and immune organ on day 56. Therefore, we conclude that the addition of PEO could improve the production performance and immune function in laying hens.

ABSTRACT Purpose To compare perioperative and pathological results in different approaches of robotic or laparoscopic radical prostatectomy. Materials and Methods We retrospectively reviewed 206 patients diagnosed with prostate cancer (PC) from June 2016 to October 2017 in the First Affiliated Hospital of Nanjing Medical University. A total of 132 cases underwent robot-assisted laparoscopic radical prostatectomy (RLRP) including 54 patients on transperitoneal robot-assisted laparoscopic radical prostatectomy (Tp-RLRP) and 78 on extraperitoneal robot-assisted laparoscopic radical prostatectomy (Ep-RLRP). Meanwhile, 74 patients performed with extraperitoneal laparoscopic radical prostatectomy (Ep-LPR) were also included. Perioperative and pathological data were compared among these groups. Results All operations were completed without conversion. There was no significant difference in basic and pathological characteristics of patients between each two groups. In Tp-RLRP vs. Ep-RLRP: Significant differences were found in the comparison in total operation time [235.98 ± 59.16 vs. 180.45 ± 50.27 min, P = 0.00], estimated blood loss (EBL) [399.07 ± 519.57 vs. 254.49 ± 308.05 mL, P = 0.0473], postoperative pelvic drainage time [5.37 ± 2.33 vs. 4.24 ± 3.08 d, P = 0.0237] and postoperative length of stay [8.15 ± 3.30 vs. 6.49 ± 3.49 d, P = 0.0068] while no significant differences were detected in other variables. In Ep-RLRP vs. Ep-LPR: Longer total operation time was observed in Ep-RLRP when compared to Ep-LPR [180.45 ± 50.27 vs. 143.80 ± 33.13 min, P = 0.000]. No significant differences were observed in other variables. Conclusion In RLRP, Ep-RLRP was proved a safe and effective approach based on the perioperative results compared to Tp-RLRP. Ep-RLRP and Ep-LPR provides equivalent perioperative and pathological outcomes.

ABSTRACT Aim: The role of low-intensity extracorporeal shock wave therapy (LI-ESWT) in erectile dysfunction (ED) is not clearly determined. The purpose of this study is to investigate the short-term efficacy and safety of LI-ESWT for ED patients. Materials and Methods: Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases. Effective rate in terms of International Index of Erectile Function-Erectile Function Domain (IIEF-EF) and Erectile Hardness Score (EHS) at about 1XSmonth after LI-ESWT was extracted from eligible studies for meta-analysis to calculate risk ratio (RR) of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment. Results: Overall fifteen studies were included in the review, of which four randomized controlled trials (RCTs) were for meta-analysis. Effective treatment was 8.31 [95°/o confidence interval (CI): 3.88-17.78] times more effective in the LI-ESWT group (n=176) than in the sham-treatment group (n= 101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95% CI: 0.74–8.45) times more in the treatment group (n= 121) than in the control group (n=89) in terms of IIEF-EF. Nine-week protocol with energy density of 0.09mJ/mm2 and 1500 pluses seemed to have better therapeutic effect than five-week protocol. No significant adverse event was reported. Conclusion: LI-ESWT, as a noninvasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is. Owing to the limited number and quality of the studies, more large-scale, well-designed and longterm follow-up time studies are needed to confirm our analysis.

ABSTRACT The objective of this work was to investigate the effect of feeding conditions on methylation status of FATP1 gene, which is an important candidate gene of Intramuscular fat and important indicator of chicken meat quality. We selected Daninghe (DNH) and Qingjiaoma (QJM) chickens under scatter-feeding and captivity-feeding conditions as experimental animals, and detected the methylation status of FATP1 genes in chicken breast muscle using Bisulfite Sequencing PCR method. The results showed that the methylation level of FATP1 in scatter-fed chicken was lower than in captivity-fed conditions in DNH and QIM chicken breast tissues; DNA methylation in the promoter and exon1 region was demonstrated to negatively regulate the expression of the FATP1 gene. These results suggested that feeding conditions affect the methylation status and expression level of FATP1, thereby affecting the Intramuscular fat content in DNH and QJM chicken breast muscle.

ABSTRACT Objective: To assess the susceptibility of the hOGG1 genetic polymorphism for bladder cancer and evaluate the impact of smoking exposure. Materials and Methods: Articles included in PubMed, Medline and Springer databases were retrieved using the following key words: “human 8-oxoguanine DNA glycosylase”, “OGG”, “OGG1”, “hOGG1”, “genetic variation”, “polymorphism” , “bladder cancer”, and “bladder carcinoma” to Meta-analysis was performed to detect whether there were differences between the bladder cancer group and the control group about the distribution of genotypes of the hOGG1 gene. Results: The results showed that there are no significant associations between the hOGG1 326Cys polymorphism and bladder cancer: GG vs. CC (OR: 1.09, 95% CI: 0.85–1.40, p=0.480); GC vs. CC (OR: 1.05, 95% CI: 0.85–1.28, p=0.662); GG+GC vs. CC (OR: 1.04, 95% CI: 0.89–1.21, p=0.619); GG vs. GC+CC(OR: 1.02, 95% CI: 0.78–1.33, p=0.888); G vs. C (OR: 1.01, 95% CI: 0.91–1.13, p=0.818). In the smoker population, no significant associations between the hOGG1 326Cys polymorphism and bladder cancer were observed for all the models. However, individuals carrying the hOGG1 Cys326Cys genotype have increased risk for bladder cancer compared to those carrying the hOGG1 Ser326Ser genotype in the non-smoker Asian population. Conclusion: The hOGG1 326Cys polymorphisms aren't a risk factor for bladder cancer, especially in the smoker population. But GG genotype is a risk factor for bladder cancer to the non-smoker Asian population compared with CC genotype.

Se estudiaron las condiciones para extraer polisacáridos de marlos de maíz dulce (SCP). Se optimizaron cuatro parámetros [relación de agua al material inicial (materia prima), concentración de enzima compuesta, temperatura de ruptura de enzimas, y duración de la ruptura de enzimas) que afectan la extracción de SCP usando metodología de superficie de respuesta (RSM). Bajo condiciones óptimas, el rendimiento de SCP fue 17,58%. SCP tuvo efectos inhibitorios en las actividades de las enzimas α-amilasa yα-glucosidasa, y el IC50 fue de 20,91 y 12,47 mg/L. SPC puede tener efectos de prevención y tratamiento de los altos niveles de glucosa en sangre luego de las comidas en la diabetes. Los efectos inhibitorios de SCP mejoraron luego del fraccionamiento, y fueron los más fuertes en la fracción SCP80. La fracción de SCP pertenece a heteropolisacáridos β-glucósidos con un grupo piran.

The conditions for extracting polysaccharides from sweet corncobs (SCP) were studied. Four parameters (ratio of water to raw material, compound enzyme concentration, temperature of enzymolysis and duration of enzymolysis) affecting the extraction of SCP were optimized using response surface methodology (RSM). Under the optimized conditions, the yield of SCP was 17.58 %. SCP had inhibitory effects on α-amylase and α-glucosidase activities, and the IC50 was 20.91 mg/mL and 12.47 mg/mL. SCP may therefore have prevention and treatment efects on postprandial hyperglycemia in diabetes. The inhibitory effects of SCP were improved after fractionation, and were strongest in the fraction SCP80. The fraction of SCP belong to β-glycosides heteropolysaccharides with a pyran group.

ABSTRACT Objective: It is agreed that methimazole (MMI) can be administered to induce hypothyroidism. However, there are conflicting data about its effect on thyroid function and development in rats through different administrations. In the present study, we established and compared differences of the rat hypothyroid model induced by MMI added to drinking water or given through an intragastric tube. Methods: Sixty-four male Wistar rats were randomly divided into seven groups. Methimazole was added to the drinking water (0.025%, 0.04% or 0.1% wt/vol), or through intragastric gavage (5 mg/100 g body weight (bw) or 8 mg/100 g bw) one time each day for 21 days. The rats were weighed every seven days. Blood samples were taken in order to detect the concentrations of serum triiodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) at the end of the experiments. Results: Our results indicate that the effect of methimazole on a rat's thyroid function and body weight is similar in both the group given 0.1% concentration in drinking water and the group which received 8 mg/100 g bw once daily through the intragastric tube. Also, a similar effect was observed in the 0.025%, 0.04% and 5 mg/100 g bw groups. Conclusion: These findings suggest that a relationship between the concentration of MMI by oral administration and the dose of it through intragastric administration could exist, and may contribute to inducing hypothyroidism in rats.

RESUMEN Objetivo: Existe acuerdo en cuando a que el metimazol (MMI) puede ser administrado para inducir hipotiroidismo. Sin embargo, hay datos contradictorios en relación con su efecto sobre la función tiroidea y el desarrollo en ratas a través de diferentes administraciones. En el estudio actual, establecimos y comparamos las diferencias del modelo de hipotiroidismo en ratas. El hipotiroidismo es inducido añadiendo MMI al agua de beber, o suministrándolo a través de un tubo intragástrico. Métodos: Sesenta y cuatro ratas Wistar machos fueron divididas aleatoriamente en siete grupos. El metimazol fue añadido al agua de beber (0.025%, 0,04% ó 0.1% p/v), o suministrado mediante sonda intragástrica (5 mg/100 g de peso corporal (pc) ó 8 mg/100 g pc) una vez cada día por 21 días. Las ratas se pesaron cada 7 días. Se tomaron muestras de sangre para detectar las concentraciones de triyodotironina (T3), tiroxina (T4) y tirotropina (TSH) en suero al final de los experimentos. Resultados: Nuestros resultados indican que el efecto del metimazol sobre la función de la tiroides y el peso corporal de una rata es similar tanto en el grupo que recibió una concentración de 0.1% en el agua de beber como en el grupo que recibió 8 mg/100 g pc una vez al día a través de un tubo intragástrico. También se observó un efecto similar en los grupos de 0.025%, 0.04% y 5 mg/100 g pc. Conclusión: Estos resultados sugieren que podría existir una relación entre la concentración de MMI mediante administración oral y la dosis de la misma a través de administración intragástrica, lo cual puede contribuir a inducir hipotiroidismo en ratas.